CN111574528B - Method for preparing medical intermediate pyranoquinoline derivative - Google Patents
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- HGFMFKSDOFFKRV-UHFFFAOYSA-N 8h-pyrano[2,3-h]quinoline Chemical class C1=CC=NC2=C(C=CCO3)C3=CC=C21 HGFMFKSDOFFKRV-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 238000000034 method Methods 0.000 title claims abstract description 20
- 239000003054 catalyst Substances 0.000 claims abstract description 69
- 238000006243 chemical reaction Methods 0.000 claims abstract description 61
- 238000010438 heat treatment Methods 0.000 claims abstract description 49
- 239000002086 nanomaterial Substances 0.000 claims abstract description 42
- 238000010992 reflux Methods 0.000 claims abstract description 36
- 239000002994 raw material Substances 0.000 claims abstract description 32
- 150000003934 aromatic aldehydes Chemical class 0.000 claims abstract description 17
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 11
- -1 methylene compound Chemical class 0.000 claims abstract description 11
- 238000002156 mixing Methods 0.000 claims abstract description 10
- 239000007787 solid Substances 0.000 claims description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 238000000967 suction filtration Methods 0.000 claims description 21
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 20
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 claims description 18
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 16
- 239000000706 filtrate Substances 0.000 claims description 13
- 239000012295 chemical reaction liquid Substances 0.000 claims description 10
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 claims description 9
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 6
- ANGDWNBGPBMQHW-UHFFFAOYSA-N methyl cyanoacetate Chemical compound COC(=O)CC#N ANGDWNBGPBMQHW-UHFFFAOYSA-N 0.000 claims description 6
- 238000001291 vacuum drying Methods 0.000 claims description 6
- YSFBEAASFUWWHU-UHFFFAOYSA-N 2,4-dichlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C(Cl)=C1 YSFBEAASFUWWHU-UHFFFAOYSA-N 0.000 claims description 4
- FPYUJUBAXZAQNL-UHFFFAOYSA-N 2-chlorobenzaldehyde Chemical compound ClC1=CC=CC=C1C=O FPYUJUBAXZAQNL-UHFFFAOYSA-N 0.000 claims description 4
- ZWUSBSHBFFPRNE-UHFFFAOYSA-N 3,4-dichlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1Cl ZWUSBSHBFFPRNE-UHFFFAOYSA-N 0.000 claims description 4
- ZETIVVHRRQLWFW-UHFFFAOYSA-N 3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(C=O)=C1 ZETIVVHRRQLWFW-UHFFFAOYSA-N 0.000 claims description 4
- ZRYZBQLXDKPBDU-UHFFFAOYSA-N 4-bromobenzaldehyde Chemical compound BrC1=CC=C(C=O)C=C1 ZRYZBQLXDKPBDU-UHFFFAOYSA-N 0.000 claims description 4
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 claims description 4
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 claims description 4
- 239000012153 distilled water Substances 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 229910052681 coesite Inorganic materials 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 229910052906 cristobalite Inorganic materials 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052682 stishovite Inorganic materials 0.000 claims description 2
- 229910052905 tridymite Inorganic materials 0.000 claims description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 claims 5
- SZVJSHCCFOBDDC-UHFFFAOYSA-N ferrosoferric oxide Chemical compound O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 claims 2
- 238000001035 drying Methods 0.000 claims 1
- 239000000543 intermediate Substances 0.000 claims 1
- 230000003197 catalytic effect Effects 0.000 abstract description 9
- 238000000746 purification Methods 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 239000000047 product Substances 0.000 description 50
- 239000002904 solvent Substances 0.000 description 33
- 239000000243 solution Substances 0.000 description 27
- 238000003756 stirring Methods 0.000 description 23
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 22
- 239000012046 mixed solvent Substances 0.000 description 22
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- HDHQZCHIXUUSMK-UHFFFAOYSA-N 4-hydroxy-2-quinolone Chemical compound C1=CC=C2C(O)=CC(=O)NC2=C1 HDHQZCHIXUUSMK-UHFFFAOYSA-N 0.000 description 15
- 238000004587 chromatography analysis Methods 0.000 description 15
- 239000000203 mixture Substances 0.000 description 14
- 238000012512 characterization method Methods 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- UMEFFYHUMOWUSG-UHFFFAOYSA-N N,N-dimethylacetamide methanol hydrate Chemical compound O.CO.CN(C)C(C)=O UMEFFYHUMOWUSG-UHFFFAOYSA-N 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 3
- GEVUHWKYEWTTMW-UHFFFAOYSA-N n,n-dimethylacetamide;methanol Chemical compound OC.CN(C)C(C)=O GEVUHWKYEWTTMW-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- GYESAYHWISMZOK-UHFFFAOYSA-N quinolin-5-ol Chemical class C1=CC=C2C(O)=CC=CC2=N1 GYESAYHWISMZOK-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- MLIREBYILWEBDM-UHFFFAOYSA-M 2-cyanoacetate Chemical compound [O-]C(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-M 0.000 description 1
- MHQLWUHTTJUNMS-UHFFFAOYSA-N 5-oxo-6H-quinoline-3-carboxylic acid Chemical compound O=C1C=2C=C(C=NC=2C=CC1)C(=O)O MHQLWUHTTJUNMS-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 238000006000 Knoevenagel condensation reaction Methods 0.000 description 1
- IOYNQIMAUDJVEI-BMVIKAAMSA-N Tepraloxydim Chemical compound C1C(=O)C(C(=N/OC\C=C\Cl)/CC)=C(O)CC1C1CCOCC1 IOYNQIMAUDJVEI-BMVIKAAMSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000005911 anti-cytotoxic effect Effects 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 229940125716 antipyretic agent Drugs 0.000 description 1
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 229910052593 corundum Inorganic materials 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- RAYLUPYCGGKXQO-UHFFFAOYSA-N n,n-dimethylacetamide;hydrate Chemical compound O.CN(C)C(C)=O RAYLUPYCGGKXQO-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 229910001845 yogo sapphire Inorganic materials 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4277—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues
- B01J2231/4288—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues using O nucleophiles, e.g. alcohols, carboxylates, esters
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/06—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing polymers
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/06—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing polymers
- B01J31/069—Hybrid organic-inorganic polymers, e.g. silica derivatized with organic groups
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01J35/00—Catalysts, in general, characterised by their form or physical properties
- B01J35/30—Catalysts, in general, characterised by their form or physical properties characterised by their physical properties
- B01J35/33—Electric or magnetic properties
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Abstract
The invention discloses a method for preparing a medical intermediate pyranoquinoline derivative, belonging to the technical field of organic synthesis. The invention relates to a method for preparing a medical intermediate pyranoquinoline derivative, which comprises the steps of respectively adding reaction raw materials of aromatic aldehyde, an active methylene compound, 4-hydroxyquinoline-2-ketone and a catalyst into a reaction solvent, uniformly mixing, and then carrying out heating reflux reaction to obtain the pyranoquinoline derivative, wherein the catalyst is a magnetic nano material catalyst, and the structural formula of the catalyst is as follows:
the technical scheme of the invention has the advantages of high utilization rate of reaction raw materials and high product yield, and the catalytic system can be recycled, thereby reducing the pollution to the environment and simplifying the product purification process.
Description
Technical Field
The present invention belongs to the field of organic synthesis technologyThe compound is a compound containing-NH2The magnetic nano material is used for catalyzing and preparing the medical intermediate pyranoquinoline derivative.
Background
Pyranoquinoline derivatives are structural units of many natural products and have a wide range of biological and pharmacological activities, such as anti-platelet aggregation, anti-cytotoxic, anti-fungal, anti-estrogen disorders, anti-hypertension, anti-diabetic etc. In addition, they can be used as insecticides, antibacterial bactericides, antipyretics, analgesics, antihistamines and the like. Therefore, the preparation of pyranoquinoline derivatives has attracted a great deal of attention from drug synthesizers.
As one of the pyranoquinoline derivatives, 2-amino-4-arylpyranoquinoline derivatives are currently mainly prepared by two methods. The first way is to use two raw materials for preparation, such as Wanxiangshan, etc. by using arylmethylenemalononitrile and 4-hydroxyquinolin-2-one as reaction raw materials and piperidine as a catalyst in ethanol, a series of 2-amino-3-cyano-4-aryl-5, 6-dihydro-4H-pyrano [3, 2-c ] can be prepared at 80 DEG C]Quinoline-5-one derivatives, mild reaction conditions and high yield in the whole preparation process (study on reaction of Arylmethylenemalononitrile with 4-hydroxyquinoline-2-one [ J ]]Organic chemistry, 2004, 24 (12): 1595 to 1597). For another example, the subject group can prepare a series of 2-amino-4-aryl-5, 6-dihydro-4H-pyrano [3, 2-c ] compounds by using s-methylenemalononitrile or 2-cyano-3-arylacrylate and 4-hydroxyquinolin-2-one as raw materials, water as solvent, and triethylbenzylammonium chloride as catalyst]Quinolin-5-one derivatives (2-amino-4-aryl-5, 6-dihydro-4H-pyrano [3, 2-c ] in aqueous phase]Quinolin-5-one derivatives [ J]Organic chemistry, 2006, 26 (2): 228 to 232). The second mode is to adopt a three-component one-pot method for preparation. For example, the Wanxiangshan subject group takes aromatic aldehyde, cyanoacetate and 4-hydroxyquinolin-2-one as reaction raw materials, KF-Al2O3As a catalyst, a series of 2-amino-4-aryl-5, 6-dihydro-4H-pyran [3, 2-c ] can be prepared in ethanol by a one-pot method]The quinoline-5-ketone-3-carboxylic ester derivative has mild reaction conditions, easy operation and high product yield in the whole preparation processEtc. (2-amino-4-aryl-5, 6-dihydro-4H-pyran [3, 2-c) under the catalysis of KF-aluminum]One-step synthesis of quinoline-5-one-3-carboxylic ester derivatives [ J]Organic chemistry, 2005, 25 (5): 579-582). For example, the foreign Senniappan Thamalai Selvi and the like can prepare 2-amino-3-acetoxy-4-benzopyran [3, 2-c ] by taking 4-hydroxyquinoline-2 (1H) -ketone, aromatic aldehyde and ethyl cyanoacetate as reaction raw materials and triethylamine as a catalyst under the assistance of microwaves]Quinolin-5 (6H) -one derivatives (Microwave solvent-free conditioning synthesis and pharmacological evaluation of pyrano [3, 2-c ]]quinolines[J]，Medicinal Chemistry Research，2012，21：2902～2910)。
However, the preparation method has many disadvantages in the industrial large-scale application process, for example, the catalyst and the reaction solvent cannot be recycled, and a large amount of waste liquid generated can pollute the environment; the preparation process is relatively complex in operation and long in time consumption; the purification of the product needs operations such as recrystallization, column chromatography and the like, and is time-consuming, labor-consuming, expensive and poor in environmental protection property; the utilization rate of reaction raw materials is low, and the atom economy is poor.
Disclosure of Invention
1. Problems to be solved
The invention aims to overcome the defects of relatively low catalytic efficiency and reaction raw material utilization rate of a catalyst, incapability of recycling the catalyst and a reaction solvent, easiness in environmental pollution and the like in the conventional preparation method of the medical intermediate pyranoquinoline derivative, and provides a method for preparing the medical intermediate pyranoquinoline derivative. The technical scheme of the invention can effectively solve the problems, the utilization rate of reaction raw materials and the yield of the product are high, the catalytic system can be recycled, the pollution to the environment is reduced, and the purification process of the product is simple.
2. Technical scheme
In order to solve the problems, the technical scheme adopted by the invention is as follows:
the invention relates to a method for preparing a medical intermediate pyranoquinoline derivative, which comprises the steps of respectively adding reaction raw materials of aromatic aldehyde, an active methylene compound, 4-hydroxyquinoline-2-ketone and a catalyst into a reaction solvent, uniformly mixing, and then carrying out heating reflux reaction to obtain the pyranoquinoline derivative, wherein the catalyst is a magnetic nano material catalyst, and the structural formula of the catalyst is as follows:
the chemical reaction formula is as follows:
wherein the ratio of the amounts of the aromatic aldehyde, the active methylene compound and the 4-hydroxyquinolin-2-one is 1: 1-1.5: the mass of the magnetic nano material catalyst in grams is 6-14% of the amount of aromatic aldehyde in millimoles, and the mixed solvent is a solution composed of methanol, dimethylacetamide and distilled water, wherein the volume ratio of methanol to dimethylacetamide to water is (1-5): 1: (1-2) the volume of the mixed solvent in ml is 5-9 times of the molar amount of the aromatic aldehyde in millimole.
Specifically, the method comprises the following steps: (1) firstly, adding a mixed solvent into a single-mouth bottle with a magnetic stirrer and a spherical condenser tube, then adding aromatic aldehyde, an active methylene compound and 4-hydroxyquinoline-2-ketone, stirring at room temperature, uniformly mixing, and finally adding a magnetic nano-material catalyst; (2) heating until the mixed solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping the temperature until the raw material point disappears (TLC detection), finishing the reaction (the reflux reaction time is 84-102 min), and turning off the stirring; (3) immediately adsorbing the magnetic nano material catalyst by using a magnet to realize the separation of the catalyst and a reaction system; (4) cooling the residual reaction liquid with the catalyst adsorbed out to room temperature, grinding the precipitated solid, standing for 8h, and performing suction filtration; (5) washing the filter residue after suction filtration with 95% ethanol water solution for three times, and vacuum drying at 85-88 deg.C for 10-12h to obtain pyranoquinoline derivatives; (6) and (3) putting the adsorbed catalyst into the filtrate after suction filtration, adding reaction raw materials of aromatic aldehyde, an active methylene compound and 4-hydroxyquinoline-2-ketone, and carrying out the next reaction according to the steps.
The aromatic aldehyde is any one of benzaldehyde, o-chlorobenzaldehyde, p-bromobenzaldehyde, p-methoxybenzaldehyde, p-methylbenzaldehyde, m-nitrobenzaldehyde, 2, 4-dichlorobenzaldehyde and 3, 4-dichlorobenzaldehyde. The active methylene compound is any one of malononitrile, methyl cyanoacetate and ethyl cyanoacetate. The preparation method of the magnetic nanomaterial catalyst used in the present invention is described in the related literature (multivinyl amine coated Fe)3O4@SiO2 magnetic microspheres for Knoevenagel condensation[J]，Chinese Journal of Catalysis，2014，35：21～27)。
3. Advantageous effects
Compared with the prior art, the invention has the beneficial effects that:
(1) the invention relates to a method for preparing a medical intermediate pyranoquinoline derivative, which takes aromatic aldehyde, an active methylene compound and 4-hydroxyquinoline-2-ketone as reaction raw materials and selects compounds containing-NH2The magnetic nano material is used as a catalyst, and the efficiency and selectivity of the catalyst for catalyzing and preparing the pyranoquinoline derivative are high, so that the reaction efficiency can be effectively improved, the generation of byproducts is inhibited, the yield and the purity of the obtained pyranoquinoline derivative are further ensured, and the reaction time is favorably shortened.
(2) The method for preparing the medical intermediate pyranoquinoline derivative adopts the mixed solution of methanol, dimethylacetamide and distilled water as a reaction solvent, and optimizes the dosage of the catalyst and the reaction solvent and the volume ratio of each component in the reaction solvent, thereby further reducing the occurrence of side reactions and giving full play to the catalytic activity of the catalyst. Meanwhile, the mixed solvent is not only used as a reaction solvent, but also has the function of a recrystallization solvent, so that the purification process of the product is simpler.
(3) According to the method for preparing the medical intermediate pyranoquinoline derivative, a catalytic system consisting of the magnetic nano material catalyst and the mixed solvent can be reused without any treatment, so that the utilization rate of reaction raw materials is improved, and the economic and environmental benefits are high.
Drawings
FIG. 1 is a table comparing the effect of the number of times the catalytic system was used on product yield and purity in example 1;
FIG. 2 is a table comparing the effect of the number of times the catalytic system was used on product yield and purity in example 7;
FIG. 3 is a table comparing the effect of the number of times the catalytic system was used on product yield and purity in example 8;
Detailed Description
Infrared spectroscopic testing of the reaction products of the following examples characterisation was carried out using an EQUINOX 55 infrared spectrometer (KBr pellet) from Bruker, Germany; the nuclear magnetic resonance instrument of AVANCE 400MHz of Germany Bruker company is adopted for the characterization of the hydrogen spectrum nuclear magnetic resonance; the high performance liquid chromatography used for the purity measurement was a UFLC-2010PLUS model from Shimadzu corporation, Japan. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
Example 1
Adding 1.0mmol of benzaldehyde, 1.0mmol of malononitrile and 1.0mmol of 4-hydroxyquinoline-2-ketone into a 50ml single-neck bottle which is filled with 5ml of mixed solvent (the volume ratio of methanol-dimethylacetamide to water is 2: 1: 1) and is provided with a spherical condenser tube and a stirrer, stirring at room temperature, uniformly mixing, and then adding 0.09g of magnetic nano material catalyst. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping the refluxes for 91min, detecting by TLC (thin-plate chromatography), and finishing the reaction when the raw material point disappears. Heating and stirring are stopped, the magnetic nano material catalyst is immediately adsorbed by a magnet, the residual reaction solution is transferred to a beaker and is gradually cooled to room temperature, a large amount of solid is precipitated, the solid is crushed, the mixture is kept stand for 8 hours and is filtered, filter residue is washed by 95 percent ethanol water solution (4ml multiplied by 3) and is dried in vacuum at 85 ℃ for 12 hours to obtain 0.29g of product, the purity of the product is 98.1 percent by high performance liquid chromatography, and the calculated yield is 91 percent. And (3) putting the adsorbed filter residue into the filtrate after suction filtration, adding benzaldehyde, malononitrile and 4-hydroxyquinoline-2-ketone, and carrying out the next reaction according to the conditions and the steps.
The characterization data of the product obtained in this example are as follows:
IR(KBr)ν：3383，3278，3137，2856，2188，1695，1593，1497，1382，1250，1164，1099，743，688cm-1；1H NMR(400MHz，DMSO-d6)：δ＝4.47(s，1H，CH)，7.15～7.31(m，9H，ArH，NH2)，7.55(t，J＝8.0Hz，1H，ArH)，7.89(d，J＝8.5Hz，1H，ArH)，11.72(s，1H，NH)。
example 2
Adding 1.0mmol of o-chlorobenzaldehyde, 1.2mmol of malononitrile and 1.0mmol of 4-hydroxyquinolin-2-one into a 50ml single-neck bottle with a spherical condenser and a stirrer, which contains 6ml of mixed solvent (the volume ratio of methanol-dimethylacetamide-water is 3: 1: 1), stirring at room temperature, uniformly mixing, and then adding 0.10g of magnetic nano material catalyst. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping the reflux for 94min, detecting by TLC (thin-plate chromatography), and ending the reaction when the raw material point disappears. Heating and stirring are stopped, the magnetic nano material catalyst is immediately adsorbed by a magnet, the residual reaction solution is transferred to a beaker and is gradually cooled to room temperature, a large amount of solid is precipitated, the solid is crushed, the mixture is kept stand for 8 hours and is filtered, filter residue is washed by 95 percent ethanol water solution (4ml multiplied by 3) and is dried in vacuum at 85 ℃ for 12 hours, 0.32g of product is obtained, the purity of the product is 98.7 percent by high performance liquid chromatography, and the calculated yield is 89 percent. And (3) putting the adsorbed filter residue into the filtrate after suction filtration, adding o-chlorobenzaldehyde, malononitrile and 4-hydroxyquinoline-2-ketone, and carrying out the next reaction according to the conditions and the steps.
The characterization data of the product obtained in this example are as follows:
IR(KBr)ν：3321，3286，3167，2993，2948，2861，2189，1662，1590，1585，1436，1318，1257，1170，1108，1031，812，760cm-1；1H NMR(400MHz，DMSO-d6)：δ＝5.05(s，1H，CH)，7.16～7.41(m，8H，ArH，NH2)，7.59～7.64(m，1H，ArH)，7.96(d，J＝7.4Hz，1H，ArH)，11.69(s，1H，NH)。
example 3
To a 50ml single neck flask with a spherical condenser and a stirrer containing 8ml of a mixed solvent (methanol-dimethylacetamide-water volume ratio of 4: 1: 2) were added 1.0mmol of p-chlorobenzaldehyde, 1.1mmol of malononitrile, and 1.0mmol of 4-hydroxyquinolin-2-one, stirred at room temperature, mixed well, and then 0.08g of a magnetic nanomaterial catalyst was added. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping the refluxes for 87min, detecting by TLC (thin-plate chromatography), and ending the reaction when the raw material point disappears. Heating and stirring are stopped, the magnetic nano material catalyst is immediately adsorbed by a magnet, the residual reaction solution is transferred to a beaker and is gradually cooled to room temperature, a large amount of solid is precipitated, the solid is crushed, the mixture is kept stand for 8 hours, suction filtration is carried out, filter residue is washed by 95% ethanol water solution (4ml multiplied by 3) and is dried in vacuum at 85 ℃ for 12 hours, 0.32g of product is obtained, the purity of the product is 99.1% by high performance liquid chromatography, and the calculated yield is 92%. And (3) putting the adsorbed filter residue into the filtrate after suction filtration, adding p-chlorobenzaldehyde, malononitrile and 4-hydroxyquinoline-2-ketone, and carrying out the next reaction according to the conditions and the steps.
The characterization data of the product obtained in this example are as follows:
IR(KBr)ν：3351，3301，3152，2937，2848，2199，1673，1595，1590，1481，1389，1254，1170，1094，1022，841，760cm-1；1H NMR(400MHz，DMSO-d6)：δ＝4.53(s，1H，CH)，7.27(d，J＝8.5Hz，2H，ArH)，7.32(s，2H，NH2)，7.36～7.41(m，4H，ArH)，7.62～7.66(m，1H，ArH)，7.96(d，J＝8.5Hz，1H，ArH)，11.80(s，1H，NH)。
example 4
To a 50ml single neck flask with a spherical condenser and a stirrer containing 7ml of a mixed solvent (methanol-dimethylacetamide-water volume ratio 5: 1: 1) were added 1.0mmol of p-methoxybenzaldehyde, 1.4mmol of malononitrile, and 1.0mmol of 4-hydroxyquinolin-2-one, stirred at room temperature, mixed well, and then 0.12g of a magnetic nanomaterial catalyst was added. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping the refluxes for 97min, detecting by TLC (thin-plate chromatography), and finishing the reaction when the raw material point disappears. Heating and stirring are stopped, the magnetic nano material catalyst is immediately adsorbed by a magnet, the residual reaction solution is transferred to a beaker and is gradually cooled to room temperature, a large amount of solid is precipitated, the solid is crushed, the mixture is kept stand for 8 hours and is filtered, filter residue is washed by 95 percent ethanol water solution (4ml multiplied by 3) and is dried in vacuum at 85 ℃ for 12 hours, 0.31g of product is obtained, the purity of the product is 98.4 percent by high performance liquid chromatography, and the calculated yield is 87 percent. And (3) putting the adsorbed filter residue into the filtrate after suction filtration, adding p-methoxybenzaldehyde, malononitrile and 4-hydroxyquinoline-2-ketone, and carrying out the next reaction according to the conditions and the steps.
The characterization data of the product obtained in this example are as follows:
IR(KBr)ν：3383，3280，3137，2853，2188，1695，1595，1497，1381，1250，1163，1098，746，689cm-1；1H NMR(400MHz，DMSO-d6)：δ＝3.68(s，3H，CH3O)，4.41(s，1H，CH)，6.80(d，J＝8.0Hz，2H，ArH)，7.07(d，J＝8.0Hz，2H，ArH)，7.16(s，2H，NH2)，7.23～7.31(m，2H，ArH)，7.51～7.58(m，1H，ArH)，7.87(d，J＝8.4Hz，1H，ArH)，11.69(s，1H，NH)。
example 5
Adding 1.0mmol of m-nitrobenzaldehyde, 1.4mmol of malononitrile and 1.0mmol of 4-hydroxyquinoline-2-ketone into a 50ml single-neck bottle which is filled with 7ml of mixed solvent (the volume ratio of methanol-dimethylacetamide to water is 4: 1: 2) and is provided with a spherical condenser tube and a stirrer, stirring at room temperature, uniformly mixing, and then adding 0.10g of magnetic nano material catalyst. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping the reflux for 95min, detecting by TLC (thin-plate chromatography), and ending the reaction when the raw material point disappears. Heating and stirring are stopped, the magnetic nano material catalyst is immediately adsorbed by a magnet, the residual reaction solution is transferred to a beaker and is gradually cooled to room temperature, a large amount of solid is precipitated at the moment, the solid is crushed, is kept stand for 8 hours, is filtered, and is washed by 95% ethanol water solution (4ml multiplied by 3) and is dried in vacuum at 85 ℃ for 12 hours to obtain 0.32g of product, the purity of the product is 97.8% by high performance liquid chromatography, and the calculated yield is 86%. And (3) putting the adsorbed filter residue into the filtrate after suction filtration, adding m-nitrobenzaldehyde, malononitrile and 4-hydroxyquinoline-2-ketone, and carrying out the next reaction according to the conditions and the steps.
The characterization data of the product obtained in this example are as follows:
IR(KBr)ν：3545，3423，3326，2999，2947，2856，2190，1668，1642，1586，1513，1436，1375，1349，1247，1170，1104，1010，898，822，754，701，678cm-1；1H NMR(400MHz，DMSO-d6)：δ＝4.75(s，1H，CH)，7.32～7.38(m，2H，ArH)，7.44(s，2H，NH2)，7.61～7.65(m，2H，ArH)，7.78(d，J＝7.8Hz，1H，ArH)，7.98(d，J＝8.6Hz，1H，ArH)，8.09(s，1H，ArH)，8.13(d，J＝8.6Hz，1H，ArH)，11.85(s，1H，NH)。
example 6
To a 50ml single neck flask with a spherical condenser and a stirrer containing 8ml of a mixed solvent (methanol-dimethylacetamide-water volume ratio 5: 1: 1) were added 1.0mmol of 2, 4-dichlorobenzaldehyde, 1.3mmol of malononitrile, 1.0mmol of 4-hydroxyquinolin-2-one, stirred at room temperature, mixed uniformly, and then 0.12g of a magnetic nanomaterial catalyst was added. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping refluxing for 99min, detecting by TLC (thin-plate chromatography), and ending the reaction when the raw material point disappears. Heating and stirring are stopped, the magnetic nano material catalyst is immediately adsorbed by a magnet, the residual reaction solution is transferred to a beaker and is gradually cooled to room temperature, a large amount of solid is precipitated, the solid is crushed, the mixture is kept stand for 8 hours and is filtered, filter residue is washed by 95 percent ethanol water solution (4ml multiplied by 3) and is dried in vacuum at 85 ℃ for 12 hours to obtain 0.36g of product, the purity of the product is 98.4 percent by high performance liquid chromatography, and the calculated yield is 91 percent. And (3) putting the adsorbed filter residue into the filtrate after suction filtration, adding 2, 4-dichlorobenzaldehyde, malononitrile and 4-hydroxyquinoline-2-ketone, and carrying out the next reaction according to the conditions and the steps.
The characterization data of the product obtained in this example are as follows:
IR(KBr)ν：3347，3311，3173，2956，2860，2201，1674，1638，1585，1482，1386，1319，1265，1188，1117，1047，858，752cm-1；1H NMR(400MHz，DMSO-d6)：δ＝5.02(s，1H，CH)，7.19～7.38(m，6H，ArH，NH2)，7.57～7.63(m，2H，ArH)，7.95(d，J＝8.6Hz，1H，ArH)，11.78(s，1H，NH)。
example 7
To a 50ml single neck flask with a spherical condenser and a stirrer containing 6ml of a mixed solvent (methanol-dimethylacetamide-water volume ratio of 3: 1: 1) were added 1.0mmol of benzaldehyde, 1.0mmol of ethyl cyanoacetate, 1.0mmol of 4-hydroxyquinolin-2-one, stirred at room temperature, mixed well, and then 0.09g of a magnetic nanomaterial catalyst was added. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping the reflux for 95min, detecting by TLC (thin-plate chromatography), and ending the reaction when the raw material point disappears. Heating and stirring are stopped, the magnetic nano material catalyst is immediately adsorbed by a magnet, the residual reaction solution is transferred to a beaker and is gradually cooled to room temperature, a large amount of solid is precipitated, the solid is crushed, the mixture is kept stand for 8 hours and is filtered, filter residue is washed by 95 percent ethanol water solution (4ml multiplied by 3) and is dried in vacuum at 85 ℃ for 12 hours, 0.32g of product is obtained, the purity of the product is 98.6 percent by high performance liquid chromatography, and the calculated yield is 87 percent. And (3) putting the adsorbed filter residue into the filtrate after suction filtration, adding benzaldehyde, ethyl cyanoacetate and 4-hydroxyquinoline-2-ketone, and carrying out the next reaction according to the conditions and the steps.
The characterization data of the product obtained in this example are as follows:
IR(KBr)ν：3434，3312，3225，3058，2974，2889，2858，1673，1617，1580，1527，1491，1442，1376，1279，1175，1093，1024，842，759，693cm-1；1H NMR(400MHz，DMSO-d6)：δ＝1.12(t，J＝7.4Hz，3H，CH3)，4.00(q，J＝7.4Hz，2H，CH2)，7.51～7.57(m，1H，ArH)，7.73(s，2H，NH2)，7.94(d，J＝8.2Hz，1H，ArH)，11.68(s，1H，NH)。
example 8
To a 50ml single neck flask with a spherical condenser and a stirrer containing 7ml of a mixed solvent (methanol-dimethylacetamide-water volume ratio of 3: 1: 1) were added 1.0mmol of p-chlorobenzaldehyde, 1.1mmol of methyl cyanoacetate, and 1.0mmol of 4-hydroxyquinolin-2-one, stirred at room temperature, mixed well, and then 0.11g of a magnetic nanomaterial catalyst was added. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping refluxing for 89min, detecting by TLC (thin-plate chromatography), and ending the reaction when the raw material point disappears. Heating and stirring are stopped, the magnetic nano material catalyst is immediately adsorbed by a magnet, the residual reaction solution is transferred to a beaker and is gradually cooled to room temperature, a large amount of solid is precipitated, the solid is crushed, the mixture is kept stand for 8 hours and is filtered, filter residue is washed by 95 percent ethanol water solution (4ml multiplied by 3) and is dried in vacuum at 85 ℃ for 12 hours to obtain 0.33g of product, the purity of the product is 98.4 percent by high performance liquid chromatography, and the calculated yield is 85 percent. And (3) putting the adsorbed filter residue into the filtrate after suction filtration, adding p-chlorobenzaldehyde, methyl cyanoacetate and 4-hydroxyquinoline-2-ketone, and carrying out the next reaction according to the conditions and the steps.
The characterization data of the product obtained in this example are as follows:
IR(KBr)ν：3449，3352，3264，2983，2902，1685，1571，1529，1485，1440，1382，1278，1236，1161，1086，1035，915，804，742cm-1；1H NMR(400MHz，DMSO-d6)：δ＝3.54(s，3H，CH3)，4.81(s，1H，CH)，7.22～7.31(m，6H，ArH)，7.52～7.58(m，1H，ArH)，7.94(d，J＝8.2Hz，1H，ArH)，7.74(s，2H，NH2)，11.73(s，1H，NH)。
example 9
To a 50ml single neck flask with a spherical condenser and a stirrer containing 7ml of a mixed solvent (methanol-dimethylacetamide-water volume ratio of 3: 1: 1) were added 1.0mmol of p-bromobenzaldehyde, 1.0mmol of ethyl cyanoacetate, 1.0mmol of 4-hydroxyquinolin-2-one, stirred at room temperature, mixed well, and then 0.10g of a magnetic nanomaterial catalyst was added. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping the refluxes for 83min, detecting by TLC (thin-plate chromatography), and finishing the reaction when the raw material point disappears. Heating and stirring are stopped, the magnetic nano material catalyst is immediately adsorbed by a magnet, the residual reaction solution is transferred to a beaker and is gradually cooled to room temperature, a large amount of solid is precipitated, the solid is crushed, the mixture is kept stand for 8 hours and is filtered, filter residue is washed by 95 percent ethanol water solution (4ml multiplied by 3) and is dried in vacuum at 85 ℃ for 12 hours to obtain 0.40g of product, the purity of the product is 98.7 percent by high performance liquid chromatography, and the calculated yield is 89 percent. And (3) putting the adsorbed filter residue into the filtrate after suction filtration, adding p-bromobenzaldehyde, ethyl cyanoacetate and 4-hydroxyquinoline-2-ketone, and carrying out the next reaction according to the conditions and the steps.
The characterization data of the product obtained in this example are as follows:
IR(KBr)ν：3392，3296，3204，3065，2947，2806，1677，1615，1588，1449，1374，1263，1213，1176，1139，1091，1025，898，866，748cm-1；1H NMR(400MHz，DMSO-d6)：δ＝1.17(t，J＝7.4Hz，3H，CH3)，4.05(q，J＝7.4Hz，2H，CH2)，4.86(s，1H，CH)，7.24(d，J＝8.6Hz，2H，ArH)，7.33(t，J＝7.8Hz，1H，ArH)，7.38(d，J＝8.2Hz，1H，ArH)，7.42(d，J＝8.6Hz，2H，ArH)，7.58～7.61(m，1H，ArH)，7.82(s，2H，NH2)，8.01(d，J＝8.2Hz，1H，ArH)，11.74(s，1H，NH)。
example 10
To a 50ml single neck flask with a spherical condenser and a stirrer containing 8ml of a mixed solvent (methanol-dimethylacetamide-water volume ratio of 4: 1: 1) were added 1.0mmol of p-tolualdehyde, 1.5mmol of methyl cyanoacetate, and 1.0mmol of 4-hydroxyquinolin-2-one, stirred at room temperature, mixed well, and then 0.13g of a magnetic nanomaterial catalyst was added. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping refluxing for 98min, detecting by TLC (thin-plate chromatography), and ending the reaction when the raw material point disappears. Heating and stirring are stopped, the magnetic nano material catalyst is immediately adsorbed by a magnet, the residual reaction solution is transferred to a beaker and is gradually cooled to room temperature, a large amount of solid is precipitated, the solid is crushed, the mixture is kept stand for 8 hours and is filtered, filter residue is washed by 95 percent ethanol water solution (4ml multiplied by 3) and is dried in vacuum at 85 ℃ for 12 hours to obtain 0.31g of product, the purity of the product is 98.2 percent by high performance liquid chromatography, and the calculated yield is 85 percent. And (3) putting the adsorbed filter residue into the filtrate after suction filtration, adding p-tolualdehyde, methyl cyanoacetate and 4-hydroxyquinoline-2-ketone, and carrying out the next reaction according to the conditions and the steps.
The characterization data of the product obtained in this example are as follows:
IR(KBr)ν：3410，3276，3189，3057，3006，2948，2845，1674，1597，1584，1437，1382，1339，1285，1178，1090，901，775，682cm-1；1H NMR(400MHz，DMSO-d6)：δ＝2.18(s，3H，CH3)，3.53(s，3H，CH3)，4.78(s，1H，CH)，6.97(d，J＝8.2Hz，2H，ArH)，7.09(d，J＝8.2Hz，2H，ArH)，7.23～7.31(m，2H，ArH)，7.51～7.57(m，1H，ArH)，7.76(s，2H，NH2)，7.94(d，J＝7.2Hz，1H，ArH)，11.72(s，1H，NH)。
example 11
To a 50ml single neck flask with a spherical condenser and a stirrer containing 9ml of a mixed solvent (methanol-dimethylacetamide-water volume ratio 5: 1: 2) were added 1.0mmol of 3, 4-dichlorobenzaldehyde, 1.5mmol of ethyl cyanoacetate, and 1.0mmol of 4-hydroxyquinolin-2-one, stirred at room temperature, mixed uniformly, and then 0.14g of a magnetic nanomaterial catalyst was added. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping refluxing for 102min, detecting by TLC (thin-plate chromatography), and ending the reaction when the raw material point disappears. Heating and stirring are stopped, the magnetic nano material catalyst is immediately adsorbed by a magnet, the residual reaction solution is transferred to a beaker and is gradually cooled to room temperature, a large amount of solid is precipitated, the solid is crushed, the mixture is kept stand for 8 hours and is filtered, filter residue is washed by 95 percent ethanol water solution (4ml multiplied by 3) and is dried in vacuum at 85 ℃ for 12 hours to obtain 0.38g of product, the purity of the product is 98.1 percent by high performance liquid chromatography, and the calculated yield is 86 percent. And (3) putting the adsorbed filter residue into the filtrate after suction filtration, adding 3, 4-dichlorobenzaldehyde, ethyl cyanoacetate and 4-hydroxyquinoline-2-ketone, and carrying out the next reaction according to the conditions and the steps.
The characterization data of the product obtained in this example are as follows:
IR(KBr)ν：3481，3397，3295，2982，3057，2853，1680，1609，1565，1523，1493，1375，1264，1244，1161，1083，1012，955，874，752cm-1；1H NMR(400MHz，DMSO-d6)：δ＝1.12(t，J＝7.2Hz，3H，CH3)，3.98(q，J＝7.2Hz，2H，CH2)，4.78(s，1H，CH)，7.11(dd，J＝8.0Hz，1.8Hz，1H，ArH)，7.25～7.33(m，2H，ArH)，7.42(d，J＝1.8Hz，1H，ArH)，7.44(d，J＝8.0Hz，1H，ArH)，7.52～7.58(m，1H，ArH)，7.81(s，2H，NH2)，7.95(d，J＝8.4Hz，1H，ArH)，11.73(s，1H，NH)。
comparative example 1
Adding 1.0mmol of benzaldehyde, 1.0mmol of malononitrile and 1.0mmol of 4-hydroxyquinoline-2-ketone into a 50ml single-neck bottle which is filled with 5ml of mixed solvent (the volume ratio of methanol-dimethylacetamide to water is 2: 1: 2) and is provided with a spherical condenser tube and a stirrer, stirring at room temperature, uniformly mixing, and then adding 0.09g of magnetic nano material catalyst. Heating in oil bath, uniformly heating until the solvent reflux (the solvent vapor does not exceed the second ball of the spherical condenser tube), maintaining reflux for 91min, and detecting by TLC (thin-plate chromatography) until the raw material point does not completely disappear. Heating and stirring are stopped, the magnetic nano material catalyst is immediately adsorbed by a magnet, the catalyst is washed by reaction liquid, the residual reaction liquid is transferred to a beaker and is gradually cooled to room temperature, a large amount of solid exists, the solid is crushed, the mixture is kept stand for 8 hours, the filtration is carried out, filter residue is washed by 95 percent ethanol water solution (4ml multiplied by 3), vacuum drying is carried out at the temperature of 85 ℃ for 12 hours, then 0.29g of product is obtained, the purity is 83.3 percent by high performance liquid chromatography, and the calculated yield is 76 percent.
Comparative example 2
Adding 1.0mmol of benzaldehyde, 1.0mmol of malononitrile and 1.0mmol of 4-hydroxyquinoline-2-ketone into a 50ml single-neck bottle which is filled with 5ml of mixed solvent (the volume ratio of methanol to dimethylacetamide is 2: 1) and is provided with a spherical condenser tube and a stirrer, stirring at room temperature, uniformly mixing, and then adding 0.09g of magnetic nano material catalyst. Heating in oil bath, uniformly heating until the solvent reflux (the solvent vapor does not exceed the second ball of the spherical condenser tube), maintaining reflux for 91min, and detecting by TLC (thin-plate chromatography) until the raw material point does not completely disappear. Heating and stirring are stopped, the magnetic nano material catalyst is immediately adsorbed by a magnet, the catalyst is washed by reaction liquid, the residual reaction liquid is transferred to a beaker and is gradually cooled to room temperature, a small amount of solid exists, the solid is crushed, the mixture is kept stand for 8 hours, suction filtration is carried out, filter residue is washed by 95% ethanol aqueous solution (4ml multiplied by 3), vacuum drying is carried out at 85 ℃ for 12 hours, then 0.22g of product is obtained, the purity of the product is 88.7% by high performance liquid chromatography, and the calculated yield is 62%.
Comparative example 3
Adding 1.0mmol of benzaldehyde, 1.0mmol of malononitrile and 1.0mmol of 4-hydroxyquinoline-2-ketone into a 50ml single-neck bottle which is filled with 5ml of mixed solvent (the volume ratio of methanol to water is 2: 1) and is provided with a spherical condenser tube and a stirrer, stirring at room temperature, uniformly mixing, and then adding 0.09g of magnetic nano material catalyst. Heating in oil bath, uniformly heating until the solvent reflux (the solvent vapor does not exceed the second ball of the spherical condenser tube), maintaining reflux for 91min, and detecting by TLC (thin-plate chromatography) until the raw material point does not completely disappear. Heating and stirring are stopped, the magnetic nano material catalyst is immediately adsorbed by a magnet, the catalyst is washed by reaction liquid, the residual reaction liquid is transferred to a beaker and is gradually cooled to room temperature, a small amount of solid exists, the solid is crushed, the mixture is kept stand for 8 hours, suction filtration is carried out, filter residue is washed by 95% ethanol water solution (4ml multiplied by 3), vacuum drying is carried out at 85 ℃ for 12 hours, then 0.15g of product is obtained, the purity of the product is 92.1% by high performance liquid chromatography, and the calculated yield is 43%.
Comparative example 4
To a 50ml single neck flask with a spherical condenser and a stirrer containing 5ml of a mixed solvent (dimethylacetamide-water volume ratio of 1: 1) were added 1.0mmol of benzaldehyde, 1.0mmol of malononitrile, and 1.0mmol of 4-hydroxyquinolin-2-one, and stirred at room temperature to form a suspension, and then 0.09g of a magnetic nanomaterial catalyst was added. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping the refluxes for 91min, and detecting by TLC (thin-plate chromatography) until the raw material amount is basically unchanged. Heating and stirring are stopped, the magnetic nano material catalyst is immediately adsorbed by a magnet, the catalyst is washed by reaction liquid, the residual reaction liquid is transferred to a beaker and is gradually cooled to room temperature, a large amount of solid exists, the solid is crushed, the mixture is kept stand for 8 hours, the filtration is carried out, filter residue is washed by 95 percent ethanol water solution (4ml multiplied by 3), vacuum drying is carried out at the temperature of 85 ℃ for 12 hours, then 0.04g of product is obtained, the purity of the product is 90.4 percent through high performance liquid chromatography, and the calculated yield is 11 percent.
The influence of the use times of the catalytic systems consisting of the mixed solvent and the magnetic nano material in the example 1, the example 7 and the example 8 on the purity and the yield of the product is respectively considered, and the results are respectively shown in the figures 1 to 3, and can be obtained by combining the data in the figures 1 to 3 and the comparative examples 1 to 4.
Claims (6)
1. A method for preparing a medical intermediate pyranoquinoline derivative is characterized by comprising the following steps: adding reaction raw materials of aromatic aldehyde, active methylene compound, 4-hydroxyquinoline-2-ketone and catalyst into a reaction solvent respectively, uniformly mixing, and then carrying out heating reflux reaction to obtain the pyranoquinoline derivative, wherein the catalyst is a magnetic nano material catalyst, specifically a polyvinylamine-coated Fe3O4@SiO2The structural formula is as follows:
the reaction solvent is a solution composed of methanol, dimethylacetamide and distilled water, wherein the volume ratio of methanol to dimethylacetamide to water is (1-5): 1: (1-2); the aromatic aldehyde is any one of benzaldehyde, o-chlorobenzaldehyde, p-bromobenzaldehyde, p-methoxybenzaldehyde, p-methylbenzaldehyde, m-nitrobenzaldehyde, 2, 4-dichlorobenzaldehyde and 3, 4-dichlorobenzaldehyde; the active methylene compound is any one of malononitrile, methyl cyanoacetate and ethyl cyanoacetate.
2. The method for preparing a pyranoquinoline derivative as a pharmaceutical intermediate according to claim 1, wherein: the mass of the catalyst in grams is 6-14% of the amount of aromatic aldehyde in millimoles.
3. The method for preparing a pyranoquinoline derivative as a pharmaceutical intermediate according to claim 1, wherein: the volume of the reaction solvent in ml is 5 to 9 times the molar amount of the aromatic aldehyde in mmol.
4. A process for producing a pyranoquinoline derivative as a pharmaceutical intermediate according to any one of claims 1 to 3, which comprises: the mass ratio of the aromatic aldehyde, the active methylene compound and the 4-hydroxyquinoline-2-ketone is 1: (1-1.5): 1.
5. the method for preparing a pyranoquinoline derivative as a pharmaceutical intermediate according to claim 4, wherein: adsorbing the magnetic nano material catalyst by using a magnet after the reaction is finished, realizing the separation of the catalyst and a reaction system, cooling the residual reaction liquid adsorbing the catalyst to room temperature, crushing the precipitated solid, standing, carrying out suction filtration, washing the filter residue obtained by suction filtration, and drying in vacuum to obtain the pyranoquinoline derivative; and (3) putting the adsorbed catalyst into the filtrate after suction filtration, adding reaction raw materials of aromatic aldehyde, an active methylene compound and 4-hydroxyquinoline-2-ketone, and carrying out the next reaction according to the steps.
6. The method for preparing a pyranoquinoline derivative as a pharmaceutical intermediate according to claim 5, wherein: washing filter residue obtained by suction filtration with 95% ethanol water solution for three times, and vacuum drying at 85-88 deg.C for 10-12 h; the reflux reaction time is 84-102 min.
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Non-Patent Citations (5)
| Title |
|---|
| 0ne-pot synthesis of pyrano[3,2-c]quinoline-2,5-dione derivatives by Fe3O4@SiO2-SO3H as an effient and reusable solid acid catalyst;Esmayeel Abbaspour-Gilandeh，等;《Monatsh Chem》;20171231;第148卷;731-738 * |
| Cobalt ferrite encapsulated in a zwitterionic chitosan derivedshell: An efficient nano‐magnetic catalyst for three-component syntheses of pyrano[3,2‐c]quinolines and spiro-oxindoles;Fatereh Asghari-Haji，等;《Appl. Organometal. Chem.》;20171231;第31卷(第12期);e3891 * |
| Magnetic Fe3O4‑supported sulfonic acid‑functionalized graphene oxide:a novel and recyclable nanocatalyst for green one‑pot synthesis of 5‑oxo‑dihydropyrano[3,2‑c]chromenes and 2‑amino‑3‑cyano‑1,4,5,6‑tetrahydropyrano[3,2‑c] quinolin‑5‑ones;Masound Khaleghi，等;《Research on Chemical Intermediates》;20190108;第45卷;2095-2118 * |
| Polyvinyl amine coated Fe3O4@SiO2 magnetic microspheres for Knoevenagel condensation;Farzad Zamani，等;《Chinese Journal of Catalysis》;20140120;第35卷(第1期);21-27 * |
| 超顺磁性纳米催化剂在有机合成中的应用;刘艳红，等;《化学进展》;20120331;第24卷(第2/3期);327-337 * |
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